A diaromatic acid ether compound, its preparation method and application, and a pharmaceutical composition.

Abstract

This invention belongs to the field of pharmaceutical biotechnology, specifically relating to a diaryl aromatic acid ether compound, its preparation method and application, and a pharmaceutical composition. This invention provides a diaryl aromatic acid ether compound and its pharmaceutically acceptable salt, wherein the diaryl aromatic acid ether compound has any one of the following structures. The diaryl aromatic acid ether compound of this invention has excellent therapeutic effects in the prevention and / or treatment of atherosclerotic cardiovascular diseases, hyperlipidemia, fatty liver disease, liver fibrosis, osteoporosis, and inflammatory-related diseases. Formula I-1, Formula I-2.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical biotechnology, specifically relating to a diaromatic acid ether compound, its preparation method and application, and a pharmaceutical composition. Background Technology

[0002] Cardiovascular disease (CVD) is the leading cause of death worldwide. Atherosclerosis is a lipid-driven chronic inflammatory disease in which lipids deposit in the lining of blood vessels, gradually forming plaques. It is the pathological basis for many cardiovascular and cerebrovascular diseases (coronary heart disease, stroke, heart failure, etc.). Hyperlipidemia, dyslipidemia, inflammation, hypertension, obesity, diabetes, and fatty liver are all important contributing factors to atherosclerotic cardiovascular disease (ASCVD). These factors interact to form metabolic syndrome. In the later stages of atherosclerosis, plaque stability decreases, increasing the risk of plaque rupture. When a plaque ruptures, it triggers thrombus formation, leading to myocardial infarction, stroke, or other cardiovascular events. Therefore, new therapeutic drugs are needed to reduce the risk of CVD.

[0003] Hyperlipidemia, also known as high blood lipids or dyslipidemia, typically refers to elevated levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or decreased levels of high-density lipoprotein cholesterol (HDL-C) in blood plasma. Excessive LDL and other substances can damage vascular endothelial cells, inducing the production of inflammatory factors and chemokines such as intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial adhesion molecule-1 (VCAM-1). Macrophages engulf excessive amounts of denatured LDL (such as ox-LDL), forming foamy macrophages, which exacerbate inflammation and promote the development of atherosclerosis. Hyperlipidemia can also cause insulin resistance (IR), worsening the progression of diabetes and fatty liver disease.

[0004] Type 2 diabetes mellitus (T2DM) is a serious chronic metabolic disease that severely threatens human health, primarily characterized by insulin resistance, progressive decline in pancreatic β-cell function, and persistent hyperglycemia. T2DM patients have an increased risk of autoimmune cardiovascular disease (ASCVD), a major cause of death in patients with T2DM and metabolic dysfunction-associated fatty liver disease (MASLD, formerly known as NAFLD). Insulin resistance (IR) is a crucial pathological basis for T2DM, cardiovascular disease, and MASLD. Hyperlipidemia exacerbates vascular damage in diabetic patients, while diabetes further aggravates dyslipidemia, creating a vicious cycle that significantly increases the risk of cardiovascular and cerebrovascular diseases. Therefore, intervention and treatment of diabetes and its complications (liver disease, cardiovascular disease, etc.) are necessary.

[0005] Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by hepatic steatosis ≥5% and the presence of at least one metabolic risk factor. It is a serious chronic liver disease with a high global incidence and significant harm, driven by insulin resistance and metabolic disorders. It can progress to metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and even liver cancer. MASH is not merely a result of hepatic lipid accumulation and inflammation; it is a complex multi-system liver disease involving hepatic and cardiovascular metabolic dysfunction, closely related to metabolic syndromes such as obesity, hypertension, diabetes, and dyslipidemia. MASLD is often accompanied by complications such as autoimmune cardiovascular disease (ASCVD), which interact to form chronic cardiovascular comorbidity. CVD is also a leading cause of death in MASH patients. Therefore, while treating MASLD, it is necessary to consider reducing the risk of CVD.

[0006] Osteoporosis is a systemic metabolic bone disease characterized by the destruction of bone microstructure caused by multiple factors (aging, medications, metabolic diseases, etc.), leading to increased bone fragility, decreased bone density and quality, and a higher risk of severe fractures. With the global aging population becoming increasingly severe, the incidence of osteoporosis is rising, impacting patients' quality of life and life expectancy, making its treatment particularly important.

[0007] ATP-binding cassette transporter A1 (ABCA1) is a 12-transmembrane ABC transporter powered by ATP hydrolysis. Its core function is to actively efflux intracellular free cholesterol and phospholipids, initiating high-density lipoprotein (HDL) production and reverse cholesterol transport. ABCA1 is closely related to the body's regulation of cholesterol homeostasis, lipid metabolism, insulin secretion, insulin resistance, and inflammation. Abnormal cholesterol metabolism is closely related to cardiovascular disease, diabetes, insulin resistance (IR), and pancreatic islet cell dysfunction. ABCA1 is a major regulator of cholesterol efflux and plays an important role in reverse cholesterol transport (RCT) and HDL production. Therefore, increasing ABCA1 expression can reduce the occurrence of ASCVD, inflammation, diabetes, and fatty liver.

[0008] The peroxisome proliferator-activated receptor (PPAR) nuclear receptor family, including PPARα, PPARβ / δ, and PPARγ, are ligand-dependent transcription factors that primarily sense fatty acids and their derivatives, regulating lipid metabolism, glucose metabolism, inflammation, and cell differentiation. They are core drug targets for metabolic diseases, playing a crucial role in regulating glucose and lipid metabolism and bone metabolism. Furthermore, PPAR activation increases ABCA1 expression. PPARα agonists, fibrates, are commonly used lipid-lowering drugs; PPARγ agonists, thiazolidinediones, are used to treat type 2 diabetes mellitus (T2DM); and PPARδ agonists show promising applications in osteoporosis and other areas. Currently, various single-agonist, dual-agonist, or pan-agonist PPARs show promising applications in T2DM, lipid-lowering, cardiovascular diseases, MASLD, and osteoporosis.

[0009] Osteoporosis protectant (OPG) is a soluble glycoprotein belonging to the tumor necrosis factor (TNF) superfamily. As a decoy receptor for nuclear factor κB receptor activator ligand (RANKL), OPG is primarily produced by osteoblasts. It competitively binds to RANKL to inhibit the RANKL-RANK receptor interaction, thereby preventing osteoclast formation and osteoclast-mediated bone resorption. OPG deficiency leads to imbalanced bone remodeling and osteoporosis; therefore, increasing OPG expression can improve bone metabolism and thus alleviate osteoporosis.

[0010] However, no target compounds with a diaryl ether structure that exhibit activities such as activating PPARα, PPARβ / δ, PPARγ, upregulating ABCA1 or OPG, and possessing good anti-inflammatory, cholesterol efflux, hepatic lipid accumulation reduction, hepatic fibrosis inhibition, glucose uptake and utilization increase, and anti-osteoporosis effects have been reported to date. Summary of the Invention

[0011] The purpose of this invention is to provide a diaromatic acid ether compound, its preparation method and application, and a pharmaceutical composition. The diaromatic acid ether compound provided by this invention has excellent effects in preventing and / or treating atherosclerotic cardiovascular diseases, hyperlipidemia, fatty liver disease, liver fibrosis, osteoporosis, and inflammatory-related diseases.

[0012] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a diaromatic acid ether compound and its pharmaceutically acceptable salt, wherein the diaromatic acid ether compound has any one of the following structures: Formula I-1, Formula I-2; Wherein: R1 is selected from any one of H atoms, halogens, C1~4 alkyl groups and C1~4 alkoxy groups; R2 is selected from any one of H atoms, -COOH, -CONHCH2COOH, and -CONHCH(CH3)COOH; R3 is selected from any one of substituted or unsubstituted phenylamino, substituted or unsubstituted pyridinamino, C3-8 cycloalkylamino, substituted or unsubstituted benzylamino, 2-thiophene methylamine, octahydrocyclopentano[c]pyrrole, substituted or unsubstituted tetrahydropyrrole, substituted or unsubstituted piperidinyl, cycloheximino, and 3-azaspiro[5.5]undecyl, wherein the substituent on the aromatic ring of the substituted phenylamino is selected from halogen, halogenated C1-10 alkyl, C1-10 alkyl, C3-10 cycloalkyl, nitro, C1-4 alkoxy, and halogenated. One or more of C1-4 alkoxy groups; the substituents on the benzylamino group are selected from one or two of C1-4 alkyl and C1-4 alkoxy groups; if R3 is selected from substituted phenylamino or substituted benzylamino, and the adjacent positions on the benzyl ring contain substituents, the adjacent substituents may or may not form a ring; the substituents on the substituted tetrahydropyrrole group are selected from one or two of C1-4 alkyl and C1-4 alkoxy groups; the substituents on the substituted piperidinyl group are selected from one or two of C1-10 alkyl and C1-4 alkoxy groups. A is selected from CH2 or C=O; M is selected from CH or N; n is selected from 2 or 3; XY is selected from C=CH or CH-CH2.

[0013] This invention provides the use of the diaromatic acid ether compounds and their pharmaceutically acceptable salts or lead compounds described above in the preparation of pharmaceuticals, wherein the pharmaceuticals are for the prevention and / or treatment of at least one of the following diseases: atherosclerotic cardiovascular disease, hyperlipidemia, fatty liver disease and liver fibrosis, diabetes caused by glucose and lipid metabolism disorders, osteoporosis, and inflammation-related diseases; the structure of the lead compound is shown below: .

[0014] The diaryl hydrocarbon acid ether compounds provided by this invention possess agonist activities such as activating PPARα, PPARβ / δ, and PPARγ, upregulating ABCA1, or upregulating OPG. Furthermore, they exhibit good anti-inflammatory effects, promote cholesterol efflux, reduce hepatic lipid accumulation, reduce liver fibrosis, and regulate bone metabolism at the cellular level. This indicates that the diaryl hydrocarbon acid ether compounds provided by this invention also have good application potential and value in the prevention and / or treatment of lipid metabolism disorders, cholesterol metabolism disorders, and inflammation-related diseases (atherosclerosis, hyperlipidemia, ASCVD, MASLD, osteoporosis, etc.). The results of the examples show that compound 46 in this invention has been found to reduce inflammation and effectively improve hyperlipidemia and hepatic lipid accumulation, and promote cholesterol efflux in a high-fat induced hyperlipidemia model in golden hamsters. Compounds 46 and 12 in Western diet-induced... ApoE - / - In a mouse model of atherosclerosis, it showed good effects in reducing plasma lipid levels, promoting cholesterol efflux, reducing hepatic lipid accumulation, and reducing atherosclerotic plaque levels, demonstrating good anti-atherosclerotic and anti-fatty liver activity, and has good potential for development into a drug for the treatment of ASCVD and MASLD. Attached Figure Description

[0015] Picture 1 The results of characterizing the endothelial cell inflammation inhibition by the compounds provided in this invention; Picture 2 Example 46: Western diet-induced ApoE - / - Aortic plaque levels in model mice; Picture 3 Example 12: Western diet-induced ApoE - / - Aortic plaque levels in model mice; Picture 4 Example 46: Western diet-induced ApoE - / - Plaque levels in the cardiac outflow tract of model mice; Picture 5 Example 12: Western diet-induced ApoE - / - Plaque levels in the cardiac outflow tract of model mice; Picture 6 Example 46: Western diet-induced ApoE - / - Liver slices from model mice; Picture 7 Example 12: Western diet-induced ApoE - / - Liver slices from model mice; Picture 8The flowchart illustrates the preparation process of the diaromatic acid ether compounds provided by this invention. Detailed Implementation

[0016] This invention provides a diaromatic acid ether compound and its pharmaceutically acceptable salt, wherein the diaromatic acid ether compound has any one of the following structures: Formula I-1, Formula I-2; Wherein: R1 is selected from any one of H atoms, halogens, C1~4 alkyl groups and C1~4 alkoxy groups; R2 is selected from any one of H atoms, -COOH, -CONHCH2COOH, and -CONHCH(CH3)COOH; R3 is selected from any one of substituted or unsubstituted phenylamino, substituted or unsubstituted pyridinamino, C3-8 cycloalkylamino, substituted or unsubstituted benzylamino, 2-thiophene methylamine, octahydrocyclopentano[c]pyrrole, substituted or unsubstituted tetrahydropyrrole, substituted or unsubstituted piperidinyl, cycloheximino, and 3-azaspiro[5.5]undecyl, wherein the substituent on the aromatic ring of the substituted phenylamino is selected from halogen, halogenated C1-10 alkyl, C1-10 alkyl, C3-10 cycloalkyl, nitro, C1-4 alkoxy, and halogenated. One or more of C1-4 alkoxy groups; the substituents on the benzylamino group are selected from one or two of C1-4 alkyl and C1-4 alkoxy groups; if R3 is selected from substituted phenylamino or substituted benzylamino, and the adjacent positions on the benzyl ring contain substituents, the adjacent substituents may or may not form a ring; the substituents on the substituted tetrahydropyrrole group are selected from one or two of C1-4 alkyl and C1-4 alkoxy groups; the substituents on the substituted piperidinyl group are selected from one or two of C1-10 alkyl and C1-4 alkoxy groups. A is selected from CH2 or C=O; M is selected from CH or N; n is selected from 2 or 3; XY is selected from C=CH or CH-CH2.

[0017] In this invention, unless otherwise specified, all raw materials / components used in the preparation are commercially available products well known to those skilled in the art.

[0018] In this invention, R1 is preferably a C1-4 alkoxy group. The C1-4 alkoxy group has been selected as a C1, C2, C3 or C4 alkoxy group.

[0019] In this invention, the substituents on the benzene ring of the substituted phenylamino group are preferably one or two of H, Cl, F, trifluoromethoxy, cyclohexyl, C1-3 alkyl, trifluoromethyl and nitro.

[0020] In this invention, the substituted phenylamino group preferably includes N-methyl-4-trifluoromethoxyaniline.

[0021] In this invention, the substituted or unsubstituted pyridine amino group in R3 is selected from pyridine-2-ylamino ( ), (5-fluoropyridin-2-yl)amino ( ), (5-methylpyridin-2-yl)amino ( Any one of them.

[0022] In this invention, when R3 is selected from substituted phenylamino, when adjacent positions on the benzene ring contain substituents, when adjacent substituents form a ring, it can be (benzo[d][1,3]dioxo-5-ylmethyl)amino.

[0023] In this invention, R3 is preferably... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Any one of them.

[0024] In this invention, the diaromatic acid ether compound has any one of the structures shown: (Example 1) (Example 2) (Example 3) (Example 4) (Example 5) (Example 6) (Example 7) (Example 8) (Example 9) (Example 10) (Example 11) (Example 12) (Example 13) (Example 14) (Example 15) (Example 16) (Example 17) (Example 18) (Example 19) (Example 20) (Example 21) (Example 22) (Example 23) (Example 24) (Example 25) (Example 26) (Example 27) (Example 28) (Example 29) (Example 30) (Example 31) (Example 32) (Example 33) (Example 34) (Example 35) (Example 36) (Example 37) (Example 38) (Example 39) (Example 40) (Example 41) (Example 42) (Example 43) (Example 44) (Example 45) (Example 46, lead compound).

[0025] In this invention, the pharmaceutically acceptable salt is preferably a triethylamine salt, a pyridine salt, an imidazole salt, a piperidine salt, or a C3-8 cycloalkylamine salt.

[0026] This invention provides a method for preparing the diaromatic acid ether compounds described in the above technical solution. Picture 8 ).

[0027] In this invention, the preparation method of the diaromatic acid ether compound with the structure shown in Formula I-1 includes the following steps: Compound 1 and compound 2 were reacted in an organic solvent under alkaline conditions to obtain compound 3; Compound 3 is reacted with 1,5-dioxaspiro[5.5]undecane-2,4-dione or 6,10-dioxaspiro[4.5]decane-7,9-dione in a solvent to obtain compound 4, which is a diaromatic acid ether compound with the structure XY of formula I-1, where XY is C=CH; compound 4 is then reduced with an alkali metal borohydride to obtain a diaromatic acid ether compound with the structure XY of formula I-1, where XY is CH-CH2.

[0028] In this invention, the preparation method of the diaromatic acid ether compound with structure I-2, where A is CH2, includes the following steps: Compound 1 and compound 2 were reacted in an organic solvent under alkaline conditions to obtain compound 3; Compound 3 was reacted with an amine compound under acidic conditions, and then a reducing agent was added to carry out a reduction reaction to obtain a diaromatic acid ether compound with the structure shown in Formula I-2, where A is CH2.

[0029] In this invention, the preparation method of the diaromatic acid ether compound with A being C=O and the structure shown in Formula I-2 includes the following steps: Compound 1 and compound 2 were reacted in an organic solvent under alkaline conditions to obtain compound 3; Compound 3 was oxidized with an oxidizing agent to form compound 8; compound 8, amine compounds and N-methylimidazole were reacted in an organic solvent to obtain a diaromatic acid ether compound with the structure shown in formula I-2, where A is C=O.

[0030] In this invention, the structural formulas of compounds 1, 2, 3, 4, and 8 are as follows: , , , , .

[0031] This invention involves reacting compound 1 and compound 2 under alkaline conditions in an organic solvent to obtain compound 3. In this invention, the raw materials for preparing compound 3 preferably include compound 1, compound 2, and an inorganic base compound. Specifically, the inorganic base compound can be potassium carbonate. The organic solvent can be N,N-dimethylformamide (DMF), and in the examples, anhydrous DMF. The molar ratio of compound 1 to compound 2 is preferably 1:2. The molar ratio of compound 1 to the inorganic base compound is preferably 1:1.2. Preferably, compound 1 and compound 2 are dissolved in an organic solvent, and then the inorganic base compound is added to carry out the reaction. The reaction temperature is preferably 75-85°C, and in the examples, it can be 80°C. The reaction time is preferably 2-4 hours, and in the examples, it can be 3 hours. After the reaction is complete, the resulting reaction solution is cooled and poured into water to precipitate a solid, yielding compound 3.

[0032] In this invention, compounds containing esters are further hydrolyzed at room temperature with 1N KOH aqueous solution, and then acidified with 1N HCl to precipitate a solid for use in the next step of the reaction; or the hydrolyzed acid is activated with HATU, condensed with glycine / alanine, and then used in the next step of the reaction.

[0033] After obtaining compound 3, the present invention reacts compound 3 with 1,5-dioxaspiro[5.5]undecane-2,4-dione or 6,10-dioxaspiro[4.5]decane-7,9-dione in a solvent to obtain compound 4, wherein compound 4 is a diaromatic acid ether compound with the structure shown in formula I-1 where XY is C=CH. In the present invention, the molar ratio of compound 3 to 1,5-dioxaspiro[5.5]undecane-2,4-dione is preferably 1:1.2. The solvent is preferably a mixture of ethanol and water. The volume ratio of ethanol to water is preferably 1:8. The reaction temperature is preferably 35~45℃, and in the examples it can be 40℃. After the reaction is completed, the present invention preferably concentrates the obtained reaction solution and then performs column chromatography purification to obtain compound 4. The eluent used for column chromatography is preferably ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is preferably 1:10.

[0034] After obtaining compound 4, the present invention reduces compound 4 using an alkali metal borohydride to obtain a diaromatic acid ether compound with the structure shown in Formula I-1, where XY is CH-CH2. In the present invention, the alkali metal borohydride can be NaBH4. The molar ratio of compound 3 to the alkali metal borohydride is preferably 1:1.2. The reduction reaction is preferably carried out by dissolving compound 4 in an organic solvent, and then adding the alkali metal borohydride under ice-water bath conditions for reduction. The organic solvent can be methanol. The reduction reaction is carried out at room temperature. The reaction is carried out under stirring, and the stirring time is preferably 1-2 hours. After the reduction reaction is completed, the present invention quenches the reaction by adding water to the obtained reduction reaction solution, and then extracts it with dichloromethane to obtain a dichloromethane extract; the dichloromethane extract is then concentrated and purified by column chromatography to obtain a diaromatic acid ether compound with the structure shown in Formula I-1. The eluent used for column chromatography purification is preferably ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is preferably 1:10.

[0035] After obtaining compound 3, the present invention reacts compound 3 with an amine compound under acidic conditions, and then adds a reducing agent to carry out a reduction reaction, to obtain a diaromatic acid ether compound with the structure shown in Formula I-2, where A is CH2. In the present invention, the molar ratio of compound 3 to the amine compound is preferably 1:1. The reducing agent can be NaBH(OAc)3. The molar ratio of compound 3 to the reducing agent is preferably 1:1.2. The present invention preferably dissolves compound 3 in an organic solvent, adds acetic acid to adjust the organic solution of compound 3 to acidity, and then adds an amine compound to carry out the reaction. The organic solvent can be dichloromethane. The reaction is carried out at room temperature. The reaction is carried out under stirring, and the reaction time is preferably 0.5-1 h. The reduction reaction is carried out at room temperature, under stirring, and the reduction reaction time is preferably 1-2 h. After the reduction reaction is completed, the reaction solution obtained in the present invention is preferably washed with water. An organic phase is obtained; the organic phase is successively concentrated and purified by column chromatography to obtain a diaromatic acid ether compound with the structure shown in Formula I-2, where A is CH2. The eluent used for column chromatography purification is preferably ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is preferably 1:10.

[0036] After obtaining compound 3, the present invention uses an oxidizing agent to oxidize compound 3 to generate compound 8. In the present invention, the oxidizing agent can be potassium permanganate. The molar ratio of compound 3 to the oxidizing agent is preferably 1:1.2. The present invention preferably dissolves compound 3 in a solvent, and then adds the oxidizing agent to carry out the oxidation reaction. The solvent is preferably water and acetone. The oxidation reaction is carried out at room temperature and under stirring conditions, and the oxidation reaction time is preferably 4-6 hours. After the oxidation reaction is completed, an oxidation reaction solution is obtained. The present invention preferably uses compound 8 obtained by filtering and concentrating the oxidation reaction solution in sequence to directly carry out the next reaction.

[0037] After obtaining compound 8, the present invention reacts compound 8, an amine compound, and N-methylimidazole in an organic solvent to obtain a bisaromatic acid ether compound with a C=O structure as shown in Formula I-2. In the present invention, the reactants preferably further include N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (TCFH). The organic solvent can be acetonitrile. The molar ratio of compound 8 to the amine compound is preferably 1:1. The molar ratio of compound 8 to N-methylimidazole is preferably 1:1. The molar ratio of compound 8 to TCFH is preferably 1:1.1. The present invention preferably dissolves compound 8, the amine compound, and N-methylimidazole in an organic solvent, and then adds TCFH to carry out the reaction. The reaction is carried out at room temperature and under stirring, and the reaction time is preferably 1-1.5 h. After the reaction is completed, the reaction solution preferably obtained in the present invention is sequentially concentrated and subjected to column chromatography to obtain a bisaromatic acid ether compound with a C=O structure as shown in Formula I-2. The eluent used for column chromatography purification is preferably ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is preferably 1:10.

[0038] The present invention relates to the use of the diaromatic acid ether compounds and their pharmaceutically acceptable salts or lead compounds in the preparation of pharmaceuticals, wherein the pharmaceuticals are for the prevention and / or treatment of at least one of the following diseases: atherosclerotic cardiovascular disease, hyperlipidemia, fatty liver disease, diabetes, osteoporosis, and inflammation-related diseases; the structure of the lead compound is shown below: .

[0039] In this invention, the atherosclerotic cardiovascular disease (ASCVD) preferably includes at least one of atherosclerosis, coronary heart disease, and heart failure, myocardial infarction, cerebral infarction and peripheral vasculitis caused by atherosclerosis.

[0040] In this invention, the hyperlipidemia preferably includes at least one of hypercholesterolemia, hypertriglyceridemia (TG), hyperLDL-C, and low HDL.

[0041] In this invention, the fatty liver disease preferably includes at least one of metabolic dysfunction-associated fatty liver disease (MASLD), simple fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and liver cancer caused by MASH.

[0042] In this invention, the diabetes is diabetes caused by disordered glucose and lipid metabolism. Preferably, the diabetes caused by disordered glucose and lipid metabolism includes at least one of type 2 diabetes (T2DM), diabetic fatty liver disease, diabetic nephropathy, and diabetic complications.

[0043] In this invention, the inflammation-related disease is preferably an inflammatory disease caused by glucose and lipid metabolism disorders and / or inflammation. The inflammatory disease caused by glucose and lipid metabolism disorders and inflammation is preferably a disease caused by high expression of inflammation-related genes such as TNF-α, IL-1β, IL-6, VCAM-1, ICAM-1, or combinations thereof. The inflammatory disease caused by glucose and lipid metabolism disorders and inflammation preferably includes at least one of atherosclerosis, hyperlipidemia, type 2 diabetes mellitus (T2DM), fatty liver disease, osteoporosis, and osteoarthritis.

[0044] This invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the above-described diaromatic ether compound, a pharmaceutically acceptable salt thereof, and a lead compound, as well as one or more pharmaceutically acceptable carriers; the structure of the lead compound is shown below: .

[0045] To further illustrate the present invention, the technical solutions provided by the present invention are described in detail below with reference to embodiments, but these should not be construed as limiting the scope of protection of the present invention. Wherein: HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

[0046] The preparation method of the compounds in the examples specifically includes the following steps: (a) Substituted benzaldehyde 1 (1 eq) and commercially available bromide 2 (1 eq) were dissolved in anhydrous DMF, and potassium carbonate (1.2 eq) was added at room temperature. The reaction was carried out at 80°C for 3 h. If compound 2 does not contain an ester group, as in Examples 7, 8, and 14; post-treatment: the reaction solution was cooled and then poured into water to precipitate solid compound 3. If bromide 2 contains a carboxyl-protected ester group, as in Examples 1, 2, 3, 6, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, and 43, it needs to be hydrolyzed in 1N KOH aqueous solution at room temperature, and then acidified with 1N HCl. The precipitated solid is used for the next reaction. Furthermore, the structures in Examples 4 and 5 contain amino acids. The hydrolyzed acid is activated with HATU, condensed with glycine / alanine, and then used for the next reaction. The yield is 17-33%.

[0047] (b) Compound 3 (1 eq) and commercially available 1,5-dioxaspiro[5.5]undecane-2,4-dione (or 6,10-dioxaspiro[4.5]decane-7,9-dione) (1.2 eq) were dissolved in a mixture of ethanol and water (v / v: 1 / 8) and reacted overnight at 40°C. The reaction mixture was then concentrated and subjected to column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain product 4 (yield: 25%~47%).

[0048] (c) Compound 4 was dissolved in methanol and NaBH4 (1.2 eq) was added under ice bath conditions. The mixture was stirred at room temperature for 2 hours. After post-treatment, the reaction was quenched with water. The system was extracted with dichloromethane, and the dichloromethane layer was directly concentrated and column chromatography (ethyl acetate: petroleum ether = 1:10) was used to obtain product 5 (yield: 38%~46%).

[0049] (d) Compound 3 (1 eq) was dissolved in dichloromethane, acetic acid was added until the system was weakly acidic, and then commercially available amine compound (1 eq) was added. After stirring at room temperature for 0.5 hours, NaBH(OAc)3 (1.2 eq) was added and stirred at room temperature for 2 hours. After post-treatment, the mixture was washed with water, and the dichloromethane layer was directly concentrated and subjected to column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain product 7 (yield: 45%~58%).

[0050] (e) Compound 3 (1 eq) was dissolved in a mixed solution of water and acetone, and potassium permanganate (1.2 eq) was added. The mixture was stirred at room temperature for 6 hours. After post-treatment, filtration, and concentration, product 8 was obtained and proceeded directly to the next step.

[0051] (f) Compound 8 (1 eq), a commercially available amine compound (1 eq), and N-methylimidazole (2 eq) were dissolved in acetonitrile, and then TCFH (1.1 eq) was added. The mixture was stirred at room temperature for 1 hour. After post-treatment, concentration, and column chromatography (ethyl acetate: petroleum ether = 1:10) were performed to give product 9 (yield: 22%–37%). See Examples 23, 24, 25, 26, 27, 28, 44, and 45.

[0052] Example 1: Preparation of 3-((4-((2,4-dioxo-1,5-dioxanespiro[5.5]undec-3-yl)methyl)-2-methoxyphenoxy)methyl)benzoic acid; Vanillin 1 (2275.5 mg, 14.955 mmol, 1 eq) was dissolved in 25 mL of dry DMF. Then, K2CO3 (4547.3 mg, 32.901 mmol, 2.2 eq) was added, and the mixture was stirred at room temperature for 10 min. Subsequently, methyl 3-bromomethylbenzoate 2 (5367.0 mg, 17.940 mmol, 1.2 eq) was dissolved in 25 mL of dry DMF. The DMF solution of methyl 3-bromomethylbenzoate was then slowly added dropwise to the DMF solution of vanillin and K2CO3 using a dropping funnel. The mixture was stirred at room temperature for 10 min, then the temperature was slowly increased to 70-80 °C, and the reaction was continued for 3 h. Under ice bath conditions, water was added to precipitate a white solid, which was then filtered to obtain a white solid.

[0053] The above-mentioned white solid (3500.0 mg, 11.667 mmol, 1 eq) was completely dissolved in 30 mL of ethanol. 25 mL of 1 N KOH aqueous solution was slowly added dropwise to the above solution using a dropping funnel. The mixture was stirred at room temperature for 5 h. After the reaction was complete, 1 N hydrochloric acid aqueous solution was slowly added dropwise using a dropping funnel under ice bath conditions. A white solid precipitated out. The addition of 1 N hydrochloric acid aqueous solution was stopped after the solid had completely precipitated. The mixture was filtered and dried to obtain white solid product 3. In a 100 mL single-necked flask, white solid 3 (3000 mg, 10.490 mmol, 1 eq) and 1,5-dioxane[5.5]undecane-2,4-dione (2316.2 mg, 12.588 mmol, 1.2 eq) were added sequentially. Then 10 mL of water and 10 mL of ethanol were added sequentially. The mixture was heated to 60 °C and reacted overnight. The mixture was evaporated to dryness and subjected to column chromatography (ethyl acetate / petroleum ether 1 / 10) to obtain compound 4. Compound 4 was dissolved in methanol. NaBH4 (476.2 mg, 12.588 mmol, 1.2 eq) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After post-treatment, the reaction was quenched with water. The system was extracted with dichloromethane, and the dichloromethane layer was directly concentrated and subjected to column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain the product in Example 1 (yield: 38%–46%). 1H NMR (600 Mz, CD3OD): δ 8.04 (s, 1H), 7.90 (brs, 1H), 7.50 (brs,1H), 7.36 (brs, 1H), 6.95 (s, 1H), 6.82 (brs, 1H), 6.77 (brs, 1H), 5.07 (s,2H), 3.82 (s, 3H), 3.46 (s, 2H), 3.35 (s, 1H), 1.96 (brs, 4H), 1.66 (brs,4H), 1.47 (brs, 2H). 13 C NMR (150 MHz, CD3OD): δ 170.05, 150.73, 146.92, 139.39, 138.64, 130.72, 129.74, 129.67, 128.83, 121.37, 115.97, 113.82, 102.98, 77.13, 72.74,56.35, 35.60, 29.94, 26.19, 23.55. MS-ESI (m / z): 453.1 (MH) - . Example 2: 3-((4-(((3-fluorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.01 (d, J = 1.9 Hz, 1H), 7.89 (dt, J = 7.7, 1.5 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.03 (q, J = 8.1Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 8.2, 2.2Hz, 1H), 6.46 (t, J = 5.9 Hz, 1H), 6.42 (dd, J = 8.3, 2.3 Hz, 1H), 6.32 (dt,J =12.5, 2.4 Hz, 1H), 6.26 (td, J = 8.4, 2.6 Hz, 1H), 5.12 (s, 2H), 4.17 (d, J = 5.5Hz, 2H), 3.76 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.27, 150.79 (d, J C-F = 11.4 Hz), 149.15,146.50, 137.78, 132.65, 131.77, 130.10 (d, J C-F = 11.0 Hz), 128.63, 128.37,119.23, 113.73, 111.55, 108.63, 101.76, 101.58, 98.51, 98.31, 69.53, 55.51,46.19. Example 3: 3-((2-methoxy-4-(((4-(trifluoromethoxy)phenyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.02 (t, J = 1.9 Hz, 1H), 7.89 (dt, J = 7.7,1.5 Hz, 1H), 7.68 - 7.66 (m, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.03 - 7.00 (m,3H), 6.97 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 8.2, 2.1 Hz, 1H), 6.62 - 6.60 (m,2H), 6.41 (br s, 1H), 5.12 (s, 2H), 4.17 - 4.16 (m, 2H), 3.76 (s, 3H). 13C NMR (126 MHz, DMSO): δ 167.16, 149.17, 147.96, 146.48, 138.37,137.88, 132.73, 131.96, 130.92, 128.70, 128.66, 128.37, 121.95, 119.18,113.76, 112.59, 111.53, 69.51, 55.51, 46.37. Example 4: Preparation of 3-((4-((2,4-dioxo-1,5-dioxanespiro[5.5]undec-3-ylidene)methyl)-2-methoxyphenoxy)methyl)benzoyl)glycine; Vanillin 1 (2275.5 mg, 14.955 mmol, 1 eq) was dissolved in 25 mL of dry DMF. Then, K2CO3 (4547.3 mg, 32.901 mmol, 2.2 eq) was added, and the mixture was stirred at room temperature for 10 min. Subsequently, methyl 3-bromomethylbenzoate 2 (5367.0 mg, 17.940 mmol, 1.2 eq) was dissolved in 25 mL of dry DMF. The DMF solution of methyl 3-bromomethylbenzoate was then slowly added dropwise to the DMF solution of vanillin and K2CO3 using a dropping funnel. The mixture was stirred at room temperature for 10 min, then the temperature was slowly increased to 70-80 °C, and the reaction was continued for 3 h. Under ice bath conditions, water was added to precipitate a white solid, which was then filtered to obtain a white solid.

[0054] The above-mentioned white solid (3500.0 mg, 11.667 mmol, 1 eq) was completely dissolved in 30 mL of ethanol. 25 mL of 1 N KOH aqueous solution was slowly added dropwise to the above solution using a dropping funnel. The mixture was stirred at room temperature for 5 h. After the reaction was complete, 1 N hydrochloric acid aqueous solution was slowly added dropwise using a dropping funnel under ice bath conditions. A white solid precipitated out. The addition of 1 N hydrochloric acid aqueous solution was stopped after the solid had completely precipitated out. The mixture was filtered and dried to obtain a white solid. This solid was dissolved in acetonitrile, and then TCFH (1.1 eq) and N-methylimidazole (2 equiv) were added. The mixture was stirred at room temperature for 0.5 h, and then glycine (1 eq) was added. The mixture was stirred at room temperature for 1 h. After post-treatment, the mixture was concentrated, and then water was added and stirred to precipitate a solid. The solid was filtered out. After drying, the solid was reacted with 1,5-dioxane[5.5]undecane-2,4-dione to prepare Example 4, following the procedure in Example 1.

[0055] 1 H NMR (600 Mz, CD3OD): δ 8.22 (s, 1H), 8.15 (d, J= 2.0 Hz, 1H), 7.91(s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.58-7.56 (m, 2H), 7.42-7.39 (m 1H), 7.05(d, J = 8.5 Hz, 1H), 5.20 (s, 2H), 3.94 (s, 2H), 3.81 (s, 3H), 1.96-1.90 (m,4H), 1.69-1.60 (m, 4H), 1.52-1.39 (m, 2H). 13 C NMR (150 MHz, CD3OD): δ 165.40, 161.94, 158.68, 155.07, 150.41,138.24, 136.01, 133.11, 131.84, 129.85, 128.14, 127.75, 126.79, 117.44,113.78, 112.84, 106.10, 71.43, 56.49, 37.21, 25.19, 23.40, 21.86. MS-ESI (m / z): 508.2 (MH) - . Example 5: 3-((4-((2,4-dioxo-1,5-dioxanespiro[5.5]undec-3-ylidene)methyl)-2-methoxyphenoxy)methyl)benzoyl)alanine, prepared by the same method as in Example 4; 1 H NMR (600 Mz, CD3OD): δ 8.27 (s, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.97(s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.63-7.62 (m, 2H), 7.49-7.45 (m 1H), 7.11(d, J = 8.5 Hz, 1H), 5.25 (s, 2H), 4.49 (brs, 1H), 3.87 (s, 3H), 2.00-1.97 (m,4H), 1.71-1.64 (m, 4H), 1.52-1.45 (m, 5H). 13C NMR (150 MHz, CD3OD): δ 192.98, 165.38, 161.91, 158.69, 155.05,150.37, 138.21, 136.10, 133.13, 131.83, 129.85, 129.82, 128.10, 127.71,126.76, 117.44, 113.74, 112.79, 106.08, 71.40, 66.85, 56.48, 49.00, 37.20,25.18, 23.39, 21.72, 18.95, 15.42. MS-ESI (m / z): 522.2 (MH) - . Example 6: 3-((2-methoxy-4-(piperidinyl-1-ylmethyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (600 Mz, CD3OD): δ 8.04 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 5.14 (s, 2H), 4.13 (s, 2H), 3.80 (s, 3H), 3.12-3.08 (m, 8H), 1.84-1.76 (m, 8H), 1.70-1.60 (m, 4H). 13 C NMR (150 MHz, CD3OD): δ 151.44, 150.61, 138.28, 131.34, 130.02,129.69, 129.23, 125.18, 123.89, 115.82, 115.34, 71.80, 61.43, 56.50, 53.55,45.51, 24.01, 23.75, 23.16, 22.95, 22.45. MS-ESI (m / z): 354.2 (MH) - . Example 7: Preparation of 3-(3-methoxy-4-(pyridin-3-ylmethoxy)benzyl)-1,5-dioxaspiro[5.5]undecane-2,4-dione; Vanillin 1 (2275.5 mg, 14.955 mmol, 1 eq) was dissolved in 25 mL of dry DMF. Then, K2CO3 (4547.3 mg, 32.901 mmol, 2.2 eq) was added, and the mixture was stirred at room temperature for 10 min. Subsequently, 3-bromomethylpyridine (1.2 eq) was dissolved in 25 mL of dry DMF, and then slowly added dropwise to the vanillin and K2CO3 DMF solution using a dropping funnel. The mixture was stirred at room temperature for 10 min, and then the temperature was slowly increased to 70-80°C, and the reaction was continued for 3 h. Under ice bath conditions, water was added to precipitate a white solid, which was filtered to obtain a white solid. After drying, the solid was reacted with 1,5-dioxane[5.5]undecane-2,4-dione according to the procedure in Example 1, and then reduced to obtain the product of Example 7. 1 H NMR (600 Mz, CD3OD): δ 8.60 (s, 1H), 8.46 (d, J = 4.8 Hz, 1H), 7.90(d, J = 7.9 Hz, 1H), 7.42 (dd, J = 7.8, 5.0 Hz, 1H), 6.96 (d, J = 1.7 Hz, 1H), 6.83(d, J = 8.2 Hz, 1H), 6.78 (dd, J = 8.2, 1.8 Hz, 2H), 5.08 (s, 2H), 3.80 (s, 3H), 3.46 (s, 2H), 1.96-1.93 (m, 4H), 1.67-1.63 (m, 4H), 1.48-1.45 (m, 2H). 13 C NMR (150 MHz, CD3OD) δ 170.03, 150.93, 149.43, 149.33, 146.45,140.04, 137.73, 135.63, 125.09, 121.38, 116.46, 113.84, 102.98, 77.06, 70.23,56.27, 35.61, 30.00, 26.20, 23.55. MS-ESI (m / z): 412.2 (M+H) + . Example 8: 3-(3-methoxy-4-(pyridin-3-ylmethoxy)benzylylene)-1,5-dioxaspiro[5.5]undecane-2,4-dione, prepared by the same method as in Example 7; 1 H NMR (600 Mz, CDCl3): δ 8.70 (d, J = 2.1 Hz, 1H), 8.60 (dd, J = 4.9, 1.6Hz, 1H), 8.32 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.59 (dd, J = 8.5, 2.1 Hz, 1H), 7.33 (dd, J = 7.8, 4.8 Hz, 1H), 6.97 (d, J = 8.4 Hz,1H), 5.26 (s, 2H), 3.95 (s, 3H), 2.02-2.00 (m, 4H), 1.76-1.72 (m, 4H), 1.52-1.48 (m, 2H). 13 C NMR (150 MHz, CDCl3): δ 164.13, 160.65, 157.66, 153.25, 150.00,149.37, 149.08, 135.37, 131.93, 131.60, 125.94, 123.80, 116.42, 112.58,111.99, 105.16, 68.63, 56.22, 36.57, 24.33, 22.35. MS-ESI (m / z): 410.1(M+H) + . Example 9: 3-((4-(((2-fluorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.01 (t, J = 1.8 Hz, 1H), 7.89 (dt, J = 7.7,1.5 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.51 (t, J= 7.7 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.99 (ddd, J = 12.3, 7.9, 1.5 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.88 - 6.84(m, 2H), 6.60 (ddd, J = 9.4, 8.1, 1.6 Hz, 1H), 6.50 (tdd, J = 7.7, 4.8, 1.6 Hz,1H), 6.05 (m, 1H), 5.10 (s, 2H), 4.25 (d, J = 6.1 Hz (2H), 3.75 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.70, 151.43 (d, J C-F = 237.3 Hz),149.66, 146.93, 138.39, 137.07 (d, J C-F = 12.2 Hz), 133.56, 132.48, 131.54,129.21, 128.93, 125.09, 119.46, 115.96 (d, J C-F = 6.8 Hz), 114.81, 114.67,114.20, 112.94 (d, J = 3.4 Hz), 111.83, 70.04, 56.02, 46.26. Example 10: 3-(4-((2,4-difluorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.02 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.08 - 7.03 (m, 2H), 7.03 (d,J = 1.6 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.85 (dd, J = 8.1, 1.6 Hz, 1H), 6.78(td, J = 8.7, 2.1 Hz, 1H), 6.58 (td, J = 9.5, 5.7 Hz, 1H), 5.97 (s, 1H), 5.11 (s,2H), 4.24 (d, J = 5.4 Hz, 2H), 3.75 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.18, 149.14, 146.42, 137.85, 133.44,132.85, 131.93, 131.04, 128.68, 128.40, 118.95, 113.65, 112.30, 111.30,110.53 (d, J C-F = 18.1 Hz), 103.38 (d, J C-F = 26.7 Hz), 69.50, 55.48, 46.06. Example 11: 3-((4-((cyclopentylamino)methyl)-2-methoxyphenoxy)-methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (600 Mz, CD3OD): δ 7.98 (s, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.47(d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.14 (s, 1H), 6.96-6.93 (m, 2H), 5.10 (s, 2H), 4.05 (s, 2H), 3.81 (s, 3H), 3.53-3.50 (m, 2H), 2.07-1.97 (m,7H), 1.79-1.67 (m, 9H). 13C NMR (150 MHz, CD3OD): δ 151.35, 150.08, 138.50, 138.09, 130.90,129.94, 129.64, 129.06, 126.22, 123.76, 115.59, 114.86, 71.91, 59.80, 56.59,53.13, 51.01, 32.05, 30.59, 25.04, 24.86, 23.49. MS-ESI (m / z): 354.2 (MH) - . Example 12: 3-((2-methoxy-4-((phenylamino)methyl)-methoxy)-methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (600 Mz, CD3OD): δ 8.08 (s, 1H), 7.93 (d, J = 6.3 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.08-7.03 (m, 2H), 6.98 (s, 1H), 6.87-6.82 (m, 2H), 6.62 (d, J = 7.7 Hz, 2H), 6.58 (t, J = 7.3 Hz, 1H), 5.06 (s, 2H), 4.19 (s, 2H), 3.77 (s, 3H). 13 C NMR (150 MHz, CD3OD) δ 151.27, 150.04, 148.21, 138.99, 135.21,132.25, 129.90, 129.31, 120.77, 118.03, 116.07, 116.05, 114.24, 112.78,72.09, 56.42, 21.61. MS-ESI (m / z): 362.2 (MH) - . Example 13: 3-(4-((2,5-difluorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Chloroform- d): δ 8.16 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 6.89 - 6.86 (m, 1H), 6.85 - 6.82 (m, 2H), 6.36 (ddd, J = 10.3, 7.0, 3.0 Hz,1H), 6.27 (ddd, J = 8.5, 5.2, 3.1 Hz, 1H), 5.16 (s, 2H), 4.23 (s, 2H), 3.88 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ) δ: 150.20, 147.52, 137.84, 132.68,131.83, 129.89, 129.18, 128.96, 119.77, 114.58, 111.38, 101.97, 99.83, 70.85,56.16, 47.73. Example 14: 3-(4-(benzyloxy)-3-methoxybenzylene)-1,5-dioxaspiro[5.5]undecane-2,4-dione, prepared by the same method as in Example 7; 1 H NMR (500 Mz, CDCl3): δ 8.31-8.30 (m, 2H), 7.56 (dd, J = 8.4, 2.1 Hz,1H), 7.44-7.42 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.27 (s, 2H), 3.96 (s, 3H), 2.01 (t, J = 6.2 Hz, 4H), 1.73(t, J = 6.1 Hz, 4H), 1.50 (q, J = 6.4 Hz, 2H). 13 C NMR (126 MHz, CDCl3): δ 164.14, 160.63, 157.78, 153.79, 149.18,135.89, 132.20, 128.81, 128.33, 127.26, 125.37, 116.19, 112.45, 111.37,104.96, 70.88, 56.12, 36.44, 24.25, 22.27. MS-ESI (m / z): 409.2 (M+H) + . Example 15: 3-((4-(azacycloheptane)-1-ylmethyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (600 Mz, CD3OD): δ 8.05 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.50(d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.00-6.95 (m, 1 H), 5.12 (s, 2H), 4.16 (s, 2H), 3.69 (s, 3H), 3.22-3.15 (m, 4H), 1.86-1.84 (m, 4H), 1.69-1.67 (m, 4H). 13 C NMR (151 MHz, MeOD): δ 174.68, 151.48, 150.47, 139.10, 138.10,130.78, 129.92, 129.65, 129.09, 125.18, 124.88, 115.52, 115.33, 71.87, 61.66,56.48, 55.24, 27.69, 24.44. MS-ESI (m / z): 368.2 (MH) - . Example 16: 3-((2-methoxy-4-(tetrahydropyrrole-1-ylmethyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1H NMR (500 Mz, CD3OD): δ 8.01 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.49(d, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.00-6.95 (m, 2H), 5.13 (s, 2H), 4.14 (s, 2H), 3.74 (s, 3H), 3.21-3.15 (m, 4H), 2.02-1.99 (m, 4H). 13 C NMR (126 MHz, MeOD): δ 174.94, 151.50, 150.29, 139.03, 138.11,130.78, 129.91, 129.68, 129.06, 126.50, 123.97, 115.51, 114.91, 71.89, 59.41,56.46, 54.44, 23.86. MS-ESI (m / z): 340.2 (MH) - . Example 17: 3-((4-(((4-cyclohexylphenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 Mz, DMSO-d6): δ 7.84 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H),7.49-7.48 (m, 1H), 7.34-7.31 (m, 1H), 6.82 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H),6.70-6.65 (m, 3H), 6.32 (d, J = 7.8 Hz, 2H), 4.92 (s, 2H), 3.95 (s, 2H), 3.57(s, 3H), 2.12-2.07 (m, 1H), 1.56-1.45 (m, 5H), 1.13-0.96 (m, 5H). 13C NMR (126 MHz, DMSO) δ 167.31, 149.26, 146.87, 146.46, 138.02,135.20, 133.72, 132.07, 131.02, 128.82, 128.46, 126.96, 119.26, 113.86,112.49, 111.60, 69.67, 55.61, 46.73, 42.99, 34.50, 26.60, 25.79. MS-ESI (m / z): 444.2 (MH) - . Example 18: 3-((4-(((4-fluorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 Mz, CDCl3): δ 8.18 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.72(d, J = 7.6 Hz, 1H), 7.56 (brs, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.94 (s, 1H), 6.90-6.85 (m, 4H), 6.59-6.57 (m, 2H), 5.18 (s, 2H), 4.21 (s, 2H), 3.88 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 171.72, 156.10 (d, J = 230.1 Hz), 149.97,147.19, 144.41, 137.83, 132.71, 129.83, 129.72, 128.96 (d, J = 29.0 Hz),119.80, 115.78, 115.61, 114.44, 114.20, 114.15, 111.51, 70.70, 55.97, 49.00.MS-ESI (m / z): 380.2 (MH) - . Example 19: 3-((2-methoxy-4-((4-methylphenyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1H NMR (500 MHz, DMSO-) d6 ): δ 8.02 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.52-7.49 (m, 1H), 7.00 (s, 1H), 6.94 (d, J = 8.1 Hz,1H), 6.85-6.82 (m, 3H), 6.49 (d, J = 8.0 Hz, 2H), 5.10 (s, 2H), 4.14 (s, 2H), 3.75 (s, 3H), 2.11 (s, 3H). 13 C NMR (126 MHz, DMSO): δ 167.33, 149.26, 146.57, 146.44, 138.03,133.65, 132.09, 131.04, 129.34, 128.81, 128.48, 124.25, 122.34, 119.29,113.86, 112.65, 111.60, 69.68, 55.62, 46.74, 20.16. MS-ESI (m / z): 376.2 (MH) - . Example 20: 3-((4-((3-azaspiro[5,5]-undecane-3-yl)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (600 Mz, CD3OD): δ 8.16 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.15 (d, J =8.2 Hz, 1H), 7.08-7.06 (m, 1H), 5.26 (s, 2H), 4.28 (s, 2H), 3.97 (s, 3H), 3.23-3.21 (m, 4H), 1.76-1.74 (m, 6H), 1.59-1.52 (m, 8H). 13 C NMR (151 MHz, MeOD): δ 150.44, 150.19, 149.51, 130.21, 128.74,128.35, 127.83, 123.73, 114.53, 70.52, 55.28, 35.40, 30.04, 26.10, 20.88. MS-ESI (m / z): 422.2 (MH) - . Example 21: 3-((4-((hexahydrocyclopentano[c]pyrrole-2(1H))-yl)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (600 Mz, CD3OD): δ 8.14 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.71(d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 7.12 (d, J =8.2 Hz, 1H), 7.06 (dd, J = 8.2, 2.0 Hz, 1H), 5.24 (s, 2H), 4.32 (s, 2H), 3.94(s, 3H), 2.98-2.84 (m, 4H), 1.87-1.55 (m, 8H). 13 C NMR (151 MHz, MeOD): δ 169.10, 150.28, 149.26, 137.43, 132.05,131.39, 128.84, 128.22, 123.70, 123.03, 114.54, 114.00, 70.28, 58.68, 57.05,55.33, 51.21, 41.83, 41.02, 31.16, 30.63, 24.93. MS-ESI (m / z): 380.2 (MH) - . Example 22: 3-((4-((7,9-dioxo-6,10-dioxaspiro[4,5]decadecane-8-ylene)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1H NMR (600 MHz, DMSO-) d6 ): δ 8.26 (s, 1H), 8.03 (s, 2H), 7.92 (d, J =7.7 Hz, 1H), 7.80 (dd, J = 8.6, 1.9 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.54 (t, J =7.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 5.33 (s, 2H), 3.81 (s, 3H), 2.14 (t, J =7.2 Hz, 4H), 1.86 – 1.70 (m, 4H). 13 C NMR (151 MHz, DMSO): δ 167.14, 163.76, 160.82, 156.64, 153.04,148.44, 136.89, 132.25, 131.12, 130.79, 129.07, 128.96, 128.62, 124.83,116.58, 113.02, 112.81, 112.30, 69.57, 55.74, 37.83, 22.89. MS-ESI (m / z):437.2 (MH) - . Example 23: Preparation of 3-(4-(2,4-difluorophenyl)carbamoyl)-2-methoxyphenoxy)methyl)benzoic acid; Intermediate 3 (1 eq) was dissolved in a mixture of water and acetone, and potassium permanganate (1.2 eq) was added. The mixture was stirred at room temperature for 6 hours. After post-treatment, filtration, and concentration, it was directly proceeded to the next step. Following the synthesis steps of Example 4, the above concentrate was activated with TCFH (1.1 eq) and N-methylimidazole (2 equiv), and then reacted with 2,4-difluoroaniline to prepare Example 23.

[0056] 1 H NMR (500 MHz, DMSO- d 6): δ 9.98 (s, 1H), 8.05 (s, 1H), 7.92 (d, J =7.7 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.60 (d, J= 7.6 Hz, 2H), 7.54 (t, J = 7.8Hz, 2H), 7.36 - 7.33 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.13 - 7.10 (m, 1H), 5.27 (s, 2H), 3.86 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.68, 165.35, 160.13 (d, J C-F = 233.2Hz), 156.68 (d, J C-F = 237.2 Hz), 151.09, 149.16, 137.78, 132.59, 131.64,129.37, 129.32, 129.16, 129.05, 126.78, 121.58, 113.13, 111.78, 111.57,105.06, 104.86, 69.84, 56.20. Example 24: 3-((4-(2,5-difluorophenyl)carbamoyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 23; 1 H NMR (500 MHz, DMSO- d 6): δ 10.05 (s, 1H), 8.05 (s, 1H), 7.92 (d, J =7.7 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.61 - 7.59 (m, 2H), 7.57 - 7.53 (m,2H), 7.35 (td, J = 9.5, 5.1 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.10 (dq, J = 8.7,5.7, 4.5 Hz, 1H), 5.28 (s, 2H), 3.86 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.67, 165.39, 158.07 (d,J C-F = 238.5Hz), 151.23, 149.15, 137.75, 132.58, 131.67, 129.31, 129.04, 126.70, 121.76,117.21 (dd, J C-F = 22.7, 9.6 Hz), 113.66, 113.45, 113.11, 111.88, 69.84, 56.21. Example 25: 3-((4-(2,3-difluorophenyl)carbamoyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 23; 1 H NMR (500 MHz, DMSO- d 6): δ 7.98 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H),7.88 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.51 (q, J = 8.0Hz, 2H), 7.43 (t, J = 7.7 Hz, 1H), 7.32 - 7.26 (m, 2H), 5.12 (s, 2H), 3.60 (s, 3H). 13 C NMR (126 MHz, MeOD): δ 166.23, 153.24, 152.28, 151.29, 150.36,149.36, 137.66, 137.41, 133.23, 132.11, 129.97, 129.31, 128.88, 128.67,128.01, 125.15, 121.98, 116.71, 116.57, 113.18, 112.36, 70.33, 55.42. Example 26: 3-((2-methoxy-4-((4-(trifluoromethyl)phenyl)carbamoyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 23; 1 H NMR (500 MHz, DMSO- d6): δ 10.41 (s, 1H), 8.06 (s, 1H), 8.00 (d, J =8.5 Hz, 2H), 7.93 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 4H), 7.62 (dd, J = 8.4, 1.9 Hz, 3H), 7.58 (d, J = 1.9 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 8.5Hz, 1H), 5.29 (s, 2H), 3.89 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.14, 165.35, 150.67, 148.68, 142.96,137.26, 132.09, 131.08, 128.86, 128.82, 128.52, 126.97, 125.89, 125.86,121.12, 120.07, 112.58, 111.43, 69.33, 55.74. Example 27: 3-((4-(4-chlorophenyl)carbamoyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 23; 1 H NMR (500 MHz, DMSO- d 6): δ 10.20 (s, 1H), 8.06 (s, 1H), 7.93 (d, J =7.7 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.59 (dd, J = 8.4,1.7 Hz, 1H), 7.56 - 7.54 (m, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz,1H), 5.28 (s, 2H), 3.88 (s, 3H). 13C NMR (126 MHz, DMSO- d 6): δ 167.15, 164.98, 150.48, 148.66, 138.25,137.29, 132.10, 131.05, 128.86, 128.82, 128.52, 128.47, 127.23, 127.07,121.88, 120.92, 112.59, 111.35, 69.32, 55.73. Example 28: The preparation method of 3-((2-methoxy-4-(methyl(4-(trifluoromethoxy)phenyl)carbamoyl)phenoxy)methyl)benzoic acid is the same as that in Example 23; 1 H NMR (500 MHz, Methanol- d 4): δ 7.95 (s, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.15 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.80 (dd, J = 8.3, 1.8 Hz, 1H), 6.76 (dd, J = 4.9, 3.2 Hz, 2H), 5.01 (s, 2H), 3.53 (s, 3H), 3.36 (s, 3H), 3.21 - 3.20 (m, 2H). 13 C NMR (126 MHz, Methanol- d 4): δ 171.02, 149.64, 148.93, 147.25,143.98, 137.33, 131.77, 131.61, 128.94, 128.59, 128.49, 128.25, 128.16,128.06, 122.21, 121.61, 112.93, 112.73, 70.00, 57.10, 54.99, 37.57. Example 29: 3-((4-((2,3-difluorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1H NMR (500 MHz, Chloroform- d ): δ 8.17 (s, 1ijH), 8.05 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 6.86 (td, J = 5.8, 2.0 Hz, 3H), 6.48 (dddd, J = 10.0, 8.5, 7.2, 1.6 Hz, 1H), 6.45- 6.42 (m, 1H), 5.19 (s, 2H), 4.29 (s, 2H), 3.89 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 171.76, 150.26, 147.49, 137.93, 132.84,132.21, 129.88, 129.23, 129.02, 124.14, 119.73, 114.65, 111.38, 107.66,105.26, 70.88, 56.17, 48.02. Example 30: 3-(4-((2,6-difluorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 8.07 (d, J = 1.9 Hz, 1H), 7.94 (dt, J =7.7, 1.5 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 6.95 (d, J =2.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.77 (ddd, J = 8.3, 6.8, 2.0 Hz, 3H), 6.66(tt, J= 8.4, 5.9 Hz, 1H), 5.07 (s, 2H), 4.33 (s, 2H), 3.78 (s, 3H). 13 C NMR (126 MHz, Methanol- d 4): δ 168.67, 155.05, 153.07, 149.88,147.03, 137.96, 134.13, 131.71, 128.78, 128.53, 128.19, 119.72, 118.08 (t, J C-F = 9.4 Hz), 114.56, 111.55, 111.11, 111.06, 110.97, 110.92, 70.57, 55.01,49.38. Example 31: 3-((2-methoxy-4-((4-(trifluoromethyl)phenyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 8.08 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H),7.64 - 7.61 (m, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.99 (s,1H), 6.93 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 8.6 Hz, 2H), 5.11 (s, 2H), 4.27 (s, 2H), 3.81 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.81, 152.15, 149.71, 147.08, 138.29,132.80, 132.29, 129.16, 128.89, 126.66, 126.63, 119.67, 114.28, 112.15,112.03, 70.06, 56.05, 46.29. Example 32: 3-((4-((4-chlorophenyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 8.09 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.99(d, J = 1.6 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 6.56(d, J = 8.8 Hz, 2H), 5.11 (s, 2H), 4.19 (s, 2H), 3.81 (s, 3H). 13 C NMR (126 MHz, Methanol- d 4): δ 150.10, 147.59, 146.91, 138.01,133.63, 131.67, 128.79, 128.53, 128.32, 128.20, 120.82, 119.36, 114.85,113.78, 111.35, 70.65, 55.09, 48.49. Example 33: 3-((2-methoxy-4-((methyl(4-(trifluoromethoxy)phenyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 8.08 (d, J = 1.9 Hz, 1H), 7.95 (d, J =7.7 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.04 (d, J= 9.1Hz, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.75 (d, J = 9.2 Hz, 2H), 6.71 (dd, J = 8.2, 2.0 Hz, 1H), 5.11 (s, 2H), 4.47 (s, 2H), 3.77 (s, 3H), 2.98 (s, 2H). 13 C NMR (126 MHz, Methanol- d 4): δ 150.18, 146.97, 137.97, 132.43,131.68, 128.80, 128.54, 128.21, 121.65, 118.87, 114.92, 112.84, 110.80,70.66, 55.96, 55.07, 37.81. Example 34: 3-((2-methoxy-4-(pyridin-2-ylamino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 8.08 (s, 1H), 7.94 (d, J = 7.1 Hz, 1H),7.90 (s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.45 (dt, J = 15.3, 7.6 Hz, 2H), 7.00 (s,1H), 6.93 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 8.1 Hz, 2H), 5.13 (s, 2H), 4.41 (s, 2H), 3.82 (s, 3H). 13C NMR (126 MHz, DMSO) δ: 167.73, 159.20, 149.58, 148.01, 146.84,138.42, 137.12, 134.19, 132.41, 131.57, 129.21, 129.17, 128.86, 119.77,114.30, 112.20, 108.66, 70.07, 56.03, 44.53. Example 35: 3-((4-((5-fluoropyridin-2-yl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 8.11 (d, J = 19.3 Hz, 1H), 7.96 (d, J =6.9 Hz, 1H), 7.83 (s, 1H), 7.64 - 7.63 (m, 1H), 7.53 - 7.42 (m, 2H), 7.29 (s,1H), 7.01 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.54 (d, J =5.9 Hz, 1H), 5.14 (s, 2H), 4.40 (s, 2H), 3.85 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ: 167.96, 156.26, 152.96 (d, J C-F = 237.8Hz), 149.58, 146.88, 138.25, 133.97, 133.94, 133.78, 132.34, 132.09, 129.15,129.09, 128.86, 125.50 (d, J C-F = 20.5 Hz), 119.78, 114.26, 112.20, 109.35,70.11, 56.03, 45.01. Example 36: 3-(2-methoxy-4-((thiophen-2-ylmethyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.01 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.38 (dd, J = 4.7, 1.5 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.96 (d, J = 4.2 Hz, 1H), 6.95 (s, 3H), 6.81 (dd, J =8.2, 1.6 Hz, 1H), 5.12 (s, 2H), 3.84 (s, 2H), 3.77 (s, 3H), 3.64 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ: 167.39, 155.40, 153.24, 149.07, 146.41,137.79, 128.60, 128.41, 126.62, 124.67, 124.54, 119.97, 113.60, 112.11,69.59, 55.47, 51.54, 46.62. Example 37: 3-(2-methoxy-4-((5-methylpyridin-2-yl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.01 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H),7.78 (s, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.20 (dd, J =8.4, 2.2 Hz, 1H), 6.98 (d,J = 1.5 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.81 - 6.78(m, 1H), 6.67 (t, J = 6.0 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 4.34(d, J = 5.9 Hz, 2H), 3.75 (s, 3H), 2.07 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 157.50, 149.56, 147.34, 146.80, 138.44,138.16, 134.41, 132.40, 129.16, 128.86, 120.27, 119.72, 114.28, 112.18,108.32, 107.15, 106.19, 70.08, 56.02, 44.74, 17.51. Example 38: 3-(2-methoxy-4-((3-nitrophenyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.01 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 2.1 Hz, 2H), 7.33(d, J = 8.1 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 1.4 Hz, 1H), 7.01 -6.98 (m, 2H), 6.90 (t, J = 5.8 Hz, 1H), 6.88 - 6.83 (m, 1H), 5.12 (s, 2H), 4.26(d, J = 5.7 Hz, 2H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.72, 150.21, 149.71, 149.26, 147.12,138.33, 132.53, 132.45, 131.56, 130.41, 129.21, 128.91, 119.78, 119.03,114.27, 112.11, 110.44, 106.16, 70.00, 56.05, 46.59. Example 39: 3-((4-(benzylamino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 8.02 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.50 (dd, J = 7.6, 1.8 Hz, 2H), 7.44 - 7.42 (m, 3H),7.38 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.97(dd, J = 8.2, 1.9 Hz, 1H), 5.14 (s, 2H), 4.20 (s, 2H), 4.15 (s, 2H), 3.82 (s, 3H). 13 C NMR (126 MHz, MeOD): δ 150.09, 148.90, 136.88, 131.56, 129.89,129.72, 129.12, 128.85, 128.64, 128.35, 127.82, 124.41, 122.54, 114.27,113.49, 70.46, 55.20, 50.57, 50.51. Example 40: 3-(2-methoxy-4-((4-methoxybenzyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1H NMR (500 MHz, Methanol- d 4): δ 8.01 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.7 Hz, 3H), 7.09 (d, J = 1.9 Hz, 1H), 7.00(d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.94 (dd, J = 8.2, 1.9 Hz, 1H), 5.15(s, 2H), 4.12 (s, 2H), 4.10 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H). 13 C NMR (126 MHz, Methanol- d 4): δ 161.10, 150.58, 149.29, 137.40,131.59, 130.69, 129.06, 128.74, 128.28, 124.68, 123.38, 122.83, 114.88,114.54, 113.86, 70.78, 55.59, 54.83, 50.67, 50.45. Example 41: 3-((4-(((benzo[d][1,3]dioxo-5-ylmethyl)amino)methyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, DMSO- d 6): δ 8.00 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.96- 6.95 (m, 2H), 6.84 (d, J = 7.9 Hz, 1H), 6.81 (dd, J= 8.2, 1.8 Hz, 1H), 6.79(dd, J = 7.9, 1.4 Hz, 1H), 5.98 (s, 2H), 5.12 (s, 2H), 3.76 (s, 2H), 3.63 (d, J =3.6 Hz, 4H). 13 C NMR (126 MHz, DMSO- d 6): δ 170.87, 167.59, 149.02, 147.17, 146.52,134.02, 131.22, 128.60, 128.41, 121.39, 120.16, 113.54, 112.25, 108.62,107.85, 100.70, 69.62, 55.44, 51.41, 51.26. Example 42: 3-((2-methoxy-4-((2-methylbenzyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 7.98 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.23 - 7.22 (m, 1H), 7.19 (d, J =7.2 Hz, 2H), 7.13 (d, J = 1.8 Hz, 1H), 6.98 - 6.96 (m, 2H), 5.10 (s, 2H), 4.17(s, 2H), 4.14 (s, 2H), 3.79 (s, 3H), 2.23 (s, 3H). 13 C NMR (126 MHz, Methanol- d4): δ 171.72, 150.47, 149.27, 137.74,137.37, 135.26, 131.06, 130.71, 130.37, 130.12, 129.63, 129.02, 128.69,128.28, 126.72, 124.44, 123.09, 114.66, 113.97, 70.67, 55.60, 51.05, 48.85,18.21. Example 43: 3-(2-methoxy-4-((3-methoxybenzyl)amino)methyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 1; 1 H NMR (500 MHz, Methanol- d 4): δ 7.96 (s, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.11(s, 1H), 7.05 (s, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.96 – 6.90 (m, 3H), 6.90 (dd, J = 8.3, 2.1 Hz, 2H), 5.06 (s, 2H), 4.12 (s, 2H), 4.09 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H). 13 C NMR (126 MHz, Methanol- d 4): δ 160.25, 150.08, 148.91, 137.20,132.73, 130.64, 130.01, 128.80, 128.45, 128.08, 124.29, 122.70, 121.79,120.69, 115.07, 114.92, 114.28, 113.71, 70.34, 55.35, 54.63, 50.58, 50.45. Example 44: 3-((4-(3-fluorophenyl)carbamoyl)-2-methoxyphenoxy)methyl)benzoic acid, prepared by the same method as in Example 23; 1 H NMR (500 MHz, DMSO- d 6): δ 10.27 (s, 1H), 8.06 (s, 1H), 7.93 (d, J =7.5 Hz, 1H), 7.76 (d, J = 11.6 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.60 (d, J = 8.1Hz, 1H), 7.58 - 7.50 (m, 3H), 7.37 (q, J = 7.7 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 5.28 (s, 2H), 3.88 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): δ 167.72, 165.68, 162.58 (d, J C-F = 241.0Hz), 151.08, 149.20, 141.61, 137.75, 132.53, 131.74, 129.29, 129.05, 127.66,121.49, 116.50, 113.09, 111.90, 110.38 (d, J C-F = 20.9 Hz), 107.49 (d, J C-F = 26.0Hz), 69.86, 56.24. Example 45: 3-((2-methoxy-4-((4-(trifluoromethoxy)phenyl)carbamoyl)phenoxy)methyl)benzoic acid, prepared by the same method as in Example 23; 1 H NMR (500 MHz, DMSO- d 6): δ 10.26 (s, 1H), 8.06 (s, 1H), 7.92 (d, J =7.7 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.71 (d, J= 7.6 Hz, 1H), 7.59 (dd, J = 8.4,1.9 Hz, 1H), 7.57 - 7.52 (m, 3H), 7.36 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.5 Hz,1H), 5.28 (s, 2H), 3.87 (s, 3H). 13 C NMR (126 MHz, DMSO): δ 167.64, 165.55, 151.04, 149.19, 144.24,139.02, 137.81, 132.62, 131.51, 129.37, 129.33, 129.03, 127.67, 122.18,121.93, 121.46, 113.11, 111.90, 69.84, 56.24. Example 46: 3-((4-((2,4-dioxo-1,5-dioxane[5.5]undecane-3-ylidene)methyl)-2-methoxyphenoxy)methyl)benzoic acid (lead compound); 1 H NMR (500 Mz, DMSO-d6): δ 8.28 (s, 1H), 8.09 (brs, 1H), 8.04 (brs,1H), 7.92 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 5.33 (s, 2H), 3.81 (s, 3H), 1.97 (brs, 4H), 1.60 (brs, 4H), 1.44 (brs, 2H). Test Example 1: Compounds upregulate ABCA1 expression. Methods: ABCA1p-LUC HepG2 cells were seeded in 96-well plates, and the compound (final concentration 10 μmol / L, 200 μL of culture medium per well) was added and incubated for 18–24 hours. Luciferase reporter gene activity was detected using a luciferase assay kit. The relative ABCA1 activity of the compound was calculated as: compound luciferase activity / dimethyl sulfoxide (DMSO) control group luciferase activity.

[0057] Results: ABCA1 plays a role in regulating cholesterol balance, lipid metabolism, promoting insulin secretion, and improving insulin resistance. Increasing ABCA1 expression can reduce the occurrence of ASCVD, inflammation, diabetes, and fatty liver. This invention uses an ABCA1 expression upregulator model to evaluate the ability of compounds to upregulate ABCA1 expression. The compounds prepared in Examples 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 26, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, and 46 have good ABCA1 upregulatory activity (≥1.5-fold, Table 1), and Examples 7, 8, 23, 24, 25, 27, 28, 43, 44, and 45 have ABCA1 upregulatory activity (1.2-1.5-fold, Table 1).

[0058] Test Example 2: Activity of Compounds in Activating PPARs Methods: HepG2 cells were seeded into 96-well white-bottom cell culture plates. After cell adhesion, plasmid transfection was performed. Lipofectamine® 2000 was diluted with Opti-MEM medium (Opti-MEM: 25 μL / well, Lipofectamine® 2000: 0.4 μL / well). PPARs and GAL4 plasmids were diluted with Opti-MEM (PPARs: GAL4 = 1:9, 200 ng / well, 25 μL / well). The diluted lipofectamine® 2000 was gently mixed with the PPARs and GAL4 plasmids and incubated at room temperature for 20 min. 50 μL of the plasmid mixture and 150 μL of medium were added to the cells and cultured for 4–6 h. The mixture was then replaced with 200 μL of the compound diluted in DMEM medium containing 5% FBS (final concentration 10 μM) and incubated for 24 h. The compound's activity in activating PPARs: compound luciferase activity value / DMSO control group luciferase activity value.

[0059] Results: PPARs are closely related to the body's regulation of glucose and lipid metabolism, insulin secretion, and insulin resistance. Activating PPARs can reduce the incidence of diabetes, ASCVD, fatty liver, and osteoporosis. This invention uses a PPARs agonist screening model to evaluate the ability of compounds to activate PPARs. The compounds prepared in Examples 1, 2, 3, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, and 46 exhibit good PPARα activating activity (≥1.5-fold, Table 1). Examples 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 2... The compounds prepared in Examples 8, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 46 exhibited good activity in activating PPARδ (≥1.5 times, Table 1), and the compounds prepared in Examples 1, 2, 3, 7, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, and 46 exhibited good activity in activating PPARγ (≥1.5 times, Table 1).

[0060] Test Example 3: Activity of Compounds to Upregulate OPG Expression Methods: OPG-Luc U-2OS cells were seeded in 96-well plates and incubated with the compound (final concentration 10 μmol / L, 200 μL of culture medium per well) for 18–24 hours. Luciferase reporter gene activity was detected using a luciferase assay kit. The relative osteoprotegerin (OPG) activity of the compound was calculated as: compound luciferase activity / dimethyl sulfoxide (DMSO) control group luciferase activity.

[0061] Results: Osteoporosis progenitor (OPG) is secreted by osteoblasts and stromal cells, inhibiting osteoclast differentiation and formation. This invention uses an OPG expression upregulator screening model to evaluate the ability of compounds to upregulate OPG expression. Compounds prepared in Examples 1, 2, 3, 6, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, and 46 exhibited good OPG upregulation activity (≥1.5-fold, Table 1), while compounds prepared in Examples 5, 16, 25, 26, 27, 43, and 45 showed OPG upregulation activity (1.2-1.5-fold, Table 1).

[0062] Table 1. Upregulation activity of compounds on ABCA1, PPAR agonist activity, and OPG upregulation activity.

[0063] Test Example 4: The ability of compounds to promote cholesterol efflux from macrophages Methods: Mouse macrophage RAW264.7 cells were seeded in 96-well plates. After cell adhesion, the compound (final concentration 10 μmol / L, 200 μL of medium per well) and 22-NBD cholesterol (final concentration 5 μmol / L) were added and incubated for 18 h. Then, ApoAⅠ (final concentration 5 μg / mL) was added and incubated for 6 h. Cell nuclei were stained with Hoechst, and high-content imaging was used to photograph the cells. Intracellular fluorescence intensity was counted. The fluorescence intensity in the model group was taken as 100%, and the content of other groups was compared with the model group.

[0064] Results Description: Macrophage cholesterol efflux helps reduce lipid accumulation within macrophages, inhibits inflammation, and has anti-atherosclerotic effects. This invention evaluated the ability of compounds to promote macrophage cholesterol efflux in vitro. Compounds prepared in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 46 exhibit cholesterol efflux-promoting activity. Table 2 shows the fluorescence intensity of 22-NBD cholesterol in each macrophage, with the content in the model group representing 100%; fluorescence values ​​lower than those in the model group indicate a cholesterol efflux-promoting effect.

[0065] Test Example 5: The ability of compounds to inhibit lipid accumulation in hepatocytes Methods: Mouse hepatocytes AML12 were seeded in 96-well plates. After cell adhesion, the compound (final concentration 10 μmol / L) and FFA (final concentration 5 μmol / L) were added and incubated for 24 h. After Oil Red staining, the cells were photographed under a microscope to evaluate the lipid accumulation in the cells.

[0066] Results: Lipid accumulation in hepatocytes helps alleviate AS. This invention evaluated the ability of compounds to reduce lipid accumulation in hepatocytes in vitro. The compounds prepared in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 46 reduced lipid accumulation in hepatocytes.

[0067] Table 2. Fluorescence intensity of 22-NBD cholesterol in macrophages and lipid content in hepatocytes.

[0068] Test Example 6: Evaluation of the anti-inflammatory activity of the compound in endothelial cells Methods: Human umbilical vein endothelial cells (HUVECs) were seeded in 6-well plates and incubated with DMSO (0.1%) or a compound (1 μM) for 18 h. Subsequently, human tumor necrosis factor (TNFα) was added to a final concentration of 10 ng / mL to stimulate the cells for 6 h. Afterward, THP-1 cells were added and co-cultured with the stimulated HUVECs for 30 min. Unattached monocytes were carefully washed away with culture medium, and monocyte adhesion was observed and photographed under a microscope.

[0069] Results: Inflammation plays a crucial role in the development and progression of inflammatory diseases such as atherosclerosis. This invention utilizes the HUVEC mononuclear cell adhesion assay to evaluate the anti-inflammatory activity of the compound in endothelial cells. Experimental results show ( Picture 1 Examples 1, 2, 3, 9, 12, 20, 36, and 46 significantly reduced the number of THP-1 monocytes adhering to endothelial cells, demonstrating good anti-inflammatory activity.

[0070] Test Example 7: Establishment and treatment of an animal model of atherosclerosis 8-week-old male ApoE - / -Atherosclerosis was established in mice by feeding them a Western diet (21% fat, 0.2% cholesterol, 49.1% carbohydrates, 19.8% protein, TP26300, Nantong Trofi Feed Technology Co., Ltd.). Healthy control mice were fed a standard maintenance diet. Different doses of Compound 46 (dissolved in 0.5% sodium carboxymethyl cellulose, CMC-Na) from Example 46 were administered by gavage at doses of 10 mg / kg (low-dose L group) and 30 mg / kg (high-dose H group). Control and model mice were administered an equal volume of 0.5% CMC-Na by gavage once daily for 12 weeks. Different doses of Compound 12 (dissolved in 0.5% CMC-Na) from Example 12 were also administered by gavage at doses of 10 mg / kg (low-dose L group) and 30 mg / kg (high-dose H group). Model mice were administered an equal volume of 0.5% CMC-Na by gavage once daily for 12 weeks.

[0071] After drug administration, fasted mice were euthanized after orbital blood collection and dissection. The entire aorta was fixed in 4% polymethanol solution, excess fat was removed, and the aortic plaques were stained and photographed using Oil Red O staining solution after longitudinal dissection. Plaque levels were calculated and statistically analyzed. Serial sections of the mouse heart outflow tract were prepared using a cryostat, stained with Oil Red O staining solution, photographed, and plaque levels were calculated and statistically analyzed. Plasma levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured. Plasma levels of inflammatory factors tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were measured using corresponding ELISA kits (Nanjing Senbeijia Biotechnology Co., Ltd.). Simultaneously, tissue TC and TG assay kits were used to measure corresponding lipid levels in mouse liver and feces. The data in this invention are expressed as mean ± standard deviation (SD), using Student's... t The analysis is performed using either a test or one-way ANOVA method. P A value <0.05 is considered statistically significant.

[0072] Results: The plaque levels in the aorta and cardiac outflow tract are the most direct and powerful indicators for evaluating the anti-atherosclerotic activity of compounds. The plaque levels in the aorta and cardiac outflow tract of mice in different treatment groups are shown in the table below. As can be seen from Tables 3 and 4, compared with the model group, Examples 46 and 12 significantly reduced HFD-induced plaque levels. ApoE - / - The plaque levels in the aorta and cardiac outflow tract of mice indicate that it has good anti-atherosclerotic activity in vivo. Picture 2 Example 46: Western diet-induced ApoE - / - Aortic plaque levels in model mice. Picture 3 Example 12: Western diet-induced ApoE - / - Plaque levels in the cardiac outflow tract of model mice. Picture 4 Example 46: Western diet-induced ApoE - / - Plaque levels in the cardiac outflow tract of model mice. Picture 5 Example 12: Western diet-induced ApoE - / - Plaque levels in the cardiac outflow tract of model mice. In Table 3, n=12-14 for each group; in Table 4, n=8 for each group. ### P <0.001 vs. control; Model.

[0073] Table 3. Western Diet-Induced Diet ApoE - / - The total length of the aorta and the level of plaque in the outflow tract of the heart in model mice (the model group was defined as 100%).

[0074] Table 4. Western diet-induced ApoE - / - The total length of the aorta and the level of plaque in the outflow tract of the heart in model mice (the model group was defined as 100%).

[0075] Examples 46 and 12 reduce Western diet-induced [the effects of diet]. ApoE - / - Mouse plasma lipid levels: This invention detected lipid and blood glucose levels in mouse plasma, as shown in Tables 5 and 6. Compared with the model group, Examples 46 and 12 significantly reduced the levels of TC, LDL-C, and blood glucose in mouse plasma, showed a decreasing trend in plasma TG, and a increasing trend in HDL, indicating a good regulatory effect on glucose and lipid metabolism, suggesting its potential application in the treatment of metabolic diseases related to glucose and lipid metabolism disorders. In Table 5, n=12-14 for each group; in Table 6, n=8 for each group. ### P <0.001 vs. control; Model.

[0076] Table 5. Western Diet-Induced Diet ApoE - / - Plasma lipid and glucose levels (mmol / L) in model mice

[0077] Table 6. Western diet-induced ApoE - / - Plasma lipid and glucose levels (mmol / L) in model mice

[0078] Examples 46 and 12 increased the Western diet-induced ApoE - / - Mouse fecal cholesterol levels: Cholesterol excretion is an important pathway for preventing atherosclerosis, regulating lipids, improving pancreatic function, and reducing hepatic lipid accumulation. This invention detected... ApoE - / - Cholesterol levels in mouse feces, as shown in Tables 7 and 8, indicate that Examples 46 and 12 can increase cholesterol excretion from the body. n=4 per group; # P <0.05 vs. control; Model.

[0079] Table 7 WD-induced ApoE - / - Total cholesterol levels in feces of model mice (μmol / g feces)

[0080] Table 8. Western diet-induced ApoE - / - Total cholesterol levels in feces of model mice (μmol / g feces)

[0081] Examples 46 and 12 reduce WD-induced ApoE - / - Mouse liver lipid levels: Hepatic lipid homeostasis plays an important role in maintaining lipid metabolism and cholesterol homeostasis in vivo. This invention used an organic solvent method to extract lipids from mouse liver, and the levels of TC and TG in mouse liver were detected using TC and TG detection kits. Compared with the model group, Examples 46 and 12 significantly reduced lipid levels in mouse liver, decreased liver damage, and reduced inflammatory cell infiltration (Tables 9 and 10). Picture 6~Picture 7 ). Picture 6 Example 46: Western diet-induced ApoE - / - Liver slices from model mice. Picture 7 Example 12: Western diet-induced ApoE - / - Liver sections from model mice. n=8 per group; ### P <0.0001 vs. control; Model.

[0082] Table 9. Western diet-induced ApoE - / - Liver lipid levels (μmol / g protein) in model mice

[0083] Table 10 Western diet-induced ApoE - / - Liver lipid levels (μmol / g protein) in model mice

[0084] Example 46 Reduces Western diet-induced ApoE - / - Mouse plasma pro-inflammatory cytokine levels: Inflammation plays a crucial role in the pathological process of atherosclerosis. This invention used ELISA to detect the levels of pro-inflammatory cytokines TNFα, IL-1β, and IL-6 in mouse serum. The results (Table 11) showed that, compared with the model group, Example 46 significantly reduced the levels of pro-inflammatory cytokines TNFα, IL-1β, and IL-6 in mouse plasma, and also exhibited good anti-inflammatory effects in mice. Each group n=12; # P <0.05, ## P <0.01 vs. control; Model.

[0085] Table 11 Western diet-induced ApoE - / - Plasma pro-inflammatory factor levels in model mice (ng / L)

[0086] Test Example 8: Evaluation of lipid-regulating activity in an HFD-induced golden hamster hyperlipidemia model (Example 46) Experimental Methods: Eight-week-old male golden hamsters were randomly divided into a control group, a model group, a low-dose L group (10 mg / kg) of the drug administered in Example 46, a high-dose H group (30 mg / kg) of the drug administered in Example 46, and a positive control group receiving fenofibrate (150 mg / kg). A lipid metabolism disorder model was established by administering a high-fat diet (HFD, TP4H100, 20% fat, 40% fructose, 0.25% cholesterol, Nantong Trofi Feed Technology Co., Ltd.) to the model group, the Example 46 group, and the positive control group receiving fenofibrate. The control group received a standard maintenance diet. After one week of successful establishment of the lipid metabolism disorder model, the appropriate dose of the drug (dissolved in 0.5% CMC-Na solution) was administered to the fenofibrate group via gavage, while the control and model groups received the same volume of 0.5% CMC-Na solution. Administration was repeated once daily for three weeks. After the administration was completed, blood and liver tissue samples were collected from each group of golden hamsters for later use. Serum levels of TC, TG, LDL-C, HDL-C, ALT, and AST were measured using a biochemical analyzer. Simultaneously, corresponding lipid levels in the liver of golden hamsters were measured using tissue TC and TG assay kits. Statistical analysis: Data from this invention are expressed as mean ± standard deviation (SD), using Student's... t The analysis can be performed using either a test or one-way ANOVA analysis method. P A value <0.05 is considered statistically significant.

[0087] Experimental Results: Example 46 reduced lipid and glucose levels in HFD-induced golden hamster serum: The present invention measured lipid and glucose levels in the serum of golden hamsters. The experimental results (Table 12) showed that, compared with the model, Example 46 significantly reduced the levels of TC, LDL-C, and glucose in the serum of golden hamsters, and reduced TG levels. The results of this invention suggest that Example 46 can exert good lipid-lowering activity in HFD-induced golden hamsters, superior to the positive control drug fenofibrate. In Table 12, n=5-6 for each group; ### P <0.001 vs. control; Model.

[0088] Table 12 HFD-induced serum lipid levels in golden hamsters (mmol / L)

[0089] Example 46: Increased FFD-Induced Fecal Cholesterol Levels in Golden Hamsters: The cholesterol levels in the feces of golden hamsters were tested in this invention. The results are shown in Table 13. Compared with the model group, Example 46 significantly increased fecal cholesterol levels, suggesting that Example 46 can increase cholesterol excretion from the body, and that a high dose is superior to the positive control drug fenofibrate. n=4 per group; ### P <0.001 vs. control; Model.

[0090] Table 13 HFD-induced total cholesterol levels in golden hamster feces (μmol / g feces)

[0091] Example 46 reduces lipid levels in HFD-induced golden hamster liver: This invention utilizes organic solvent extraction to determine TC and TG levels in the liver, as shown in Table 14. Example 46 significantly reduces TC and TG levels in the liver of golden hamsters, indicating that Example 46 has good inhibitory activity against HFD-induced lipid accumulation in the liver of golden hamsters. (n=5-6 per group) # P <0.05, ### P <0.001 vs. control; Model.

[0092] Table 14. Lipid levels (μmol / g protein) in HFD-induced golden hamster liver

[0093] In summary, Examples 46 and 12 can upregulate ABCA1 expression, activate PPARs, and upregulate OPG expression, thus exhibiting a good regulatory effect on glucose, lipid, and bone metabolism disorders. This is manifested in reducing hyperlipidemia, decreasing plaque area, inhibiting inflammation, promoting cholesterol efflux, reducing hepatic lipid accumulation, and lowering blood sugar. These effects can be used to treat atherosclerosis, hyperlipidemia, type 2 diabetes mellitus (T2DM), fatty liver disease, osteoporosis, metabolic diseases caused by glucose and lipid metabolism disorders, and diseases caused by inflammation, demonstrating good application potential and value.

[0094] As demonstrated by the above examples, the diaryl hydrocarbon ether compounds provided by this invention possess activities such as upregulating ABCA1, activating PPARα, PPARβ / δ and PPARγ, and upregulating OPG. Furthermore, they exhibit good anti-inflammatory effects, promote cholesterol efflux, reduce lipid accumulation in hepatocytes, and combat osteoporosis at the cellular level. The results of the examples show that the compounds in this invention have been found to reduce inflammation, lower blood sugar, and effectively improve hyperlipidemia and liver lipid accumulation in a high-fat induced golden hamster model. Examples 46 and 12 show effects induced by a Western diet. ApoE - / - In a mouse model of atherosclerosis, it showed good effects in reducing plasma lipid levels, lowering blood sugar, promoting cholesterol efflux, reducing hepatic lipid accumulation and inflammation, and reducing atherosclerotic plaque levels. It demonstrated good anti-atherosclerotic and fatty liver-improving activity, and has good potential for development into a drug for the treatment of atherosclerotic cardiovascular disease and MASLD.

[0095] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A diaromatic acid ether compound and its pharmaceutically acceptable salt, characterized in that, The diaromatic acid ether compound has any one of the following structures: Equation I-1, Equation I-2; Wherein: R1 is selected from any one of H atoms, halogens, C1~4 alkyl groups and C1~4 alkoxy groups; R2 is selected from any one of H atoms, -COOH, -CONHCH2COOH, and -CONHCH(CH3)COOH; R3 is selected from any one of substituted or unsubstituted phenylamino, substituted or unsubstituted pyridinamino, C3-8 cycloalkylamino, substituted or unsubstituted benzylamino, 2-thiophene methylamine, octahydrocyclopentano[c]pyrrole, substituted or unsubstituted tetrahydropyrrole, substituted or unsubstituted piperidinyl, cycloheximino, and 3-azaspiro[5.5]undecyl, wherein the substituent on the aromatic ring of the substituted phenylamino is selected from halogen, halogenated C1-10 alkyl, C1-10 alkyl, C3-10 cycloalkyl, nitro, C1-4 alkoxy, and halogenated. One or more of C1-4 alkoxy groups; the substituents on the benzylamino group are selected from one or two of C1-4 alkyl and C1-4 alkoxy groups; if R3 is selected from substituted phenylamino or substituted benzylamino, and the adjacent positions on the benzyl ring contain substituents, the adjacent substituents may or may not form a ring; the substituents on the substituted tetrahydropyrrole group are selected from one or two of C1-4 alkyl and C1-4 alkoxy groups; the substituents on the substituted piperidinyl group are selected from one or two of C1-10 alkyl and C1-4 alkoxy groups. A is selected from CH2 or C=O; M is selected from CH or N; n is selected from 2 or 3; XY is selected from C=CH or CH-CH2.

2. The diaromatic acid ether compound and its pharmaceutically acceptable salt according to claim 1, characterized in that, The substituents on the benzene ring of the substituted phenylamino group are selected from one or two of Cl, F, trifluoromethoxy, cyclohexyl, trifluoromethyl and nitro; the substituted or unsubstituted pyridineamino group is selected from pyridin-2-ylamino, (5-fluoropyridin-2-yl)amino or (5-methylpyridin-2-yl)amino.

3. The diaromatic acid ether compound and its pharmaceutically acceptable salt according to claim 1 or 2, characterized in that, The diaromatic acid ether compound has any one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. The diaromatic acid ether compound and its pharmaceutically acceptable salt according to claim 1, characterized in that, The pharmaceutically acceptable salt is selected from triethylamine salt, ethylenediamine salt, morpholine salt, tert-butylamine salt, pyridine salt, imidazole salt, piperidine salt, or C3-8 cycloalkylamine salt.

5. The method for preparing the diaromatic acid ether compound according to any one of claims 1 to 3, characterized in that, Includes the following steps: Compound 1 and compound 2 were reacted in an organic solvent under alkaline conditions to obtain compound 3; Compound 3 was reacted with 1,5-dioxaspiro[5.5]undecane-2,4-dione or 6,10-dioxaspiro[4.5]decane-7,9-dione in a solvent to give compound 4, which is a diaromatic acid ether compound with XY as C=CH as shown in Formula I-1; Compound 4 was then reduced with an alkali metal borohydride to give a diaromatic acid ether compound with XY as CH-CH2 as shown in Formula I-1. Compound 3 was reacted with an amine compound under acidic conditions, and then a reducing agent was added to carry out a reduction reaction to obtain a diaromatic acid ether compound with the structure shown in formula I-2, where A is CH2. Compound 3 was oxidized with an oxidizing agent to generate compound 8; compound 8, amine compounds and N-methylimidazole were reacted in an organic solvent to obtain a diaromatic acid ether compound with A as C=O and the structure shown in formula I-2. 、 、 、 、 。 6. The use of the diaromatic acid ether compound according to any one of claims 1 to 3 and its pharmaceutically acceptable salt or lead compound in the preparation of a medicament, characterized in that, The drug is for the prevention and / or treatment of at least one of the following diseases: atherosclerotic cardiovascular disease, hyperlipidemia, fatty liver disease, diabetes, osteoporosis, and inflammation-related diseases; the structure of the lead compound is shown below: 。 7. The use according to claim 6, characterized in that, The atherosclerotic cardiovascular disease includes at least one of atherosclerosis, coronary heart disease, and heart failure, myocardial infarction, cerebral infarction, and peripheral vasculitis caused by atherosclerotic cardiovascular disease; the hyperlipidemia includes at least one of hypercholesterolemia, hypertriglyceridemia, hyperLDL-Cemia, and low HDL.

8. The use according to claim 6, characterized in that, The fatty liver disease includes at least one of the following: metabolic dysfunction-related fatty liver disease, simple fatty liver disease, metabolic dysfunction-related steatohepatitis, liver fibrosis, and liver cancer that develops from the progression of metabolic dysfunction-related fatty liver disease.

9. The use according to claim 6, characterized in that, The diabetes caused by the glucose and lipid metabolism disorder includes at least one of type 2 diabetes, diabetic fatty liver disease, diabetic nephropathy, and diabetic complications; the diabetes is diabetes caused by the glucose and lipid metabolism disorder; the inflammation-related disease is an inflammatory disease caused by the glucose and lipid metabolism disorder and / or inflammation.

10. A pharmaceutical composition, characterized in that, The invention comprises one or more of the following: a diaromatic acid ether compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, and a lead compound, and one or more pharmaceutically acceptable carriers; the structure of the lead compound is shown below: 。

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